Current treatment approaches for osteogenesis imperfecta (OI) are focused on inhibition of osteoclast-driven bone resorption. Over the last decade, bisphosphonate therapy has improved the quality of life for OI patients. Although the success of this therapy in OI has been well documented, some of the potential negative effects of bisphosphonates include decreased bone remodeling, reduced growth plate cartilage resorption, delayed healing of osteotomy sites and atypical femoral fractures. Recent studies by our group and others have indicated a role for inflammatory molecules in the pathophysiology of OI. It has been confirmed in different pathological conditions that certain proinflammatory cytokines, such as TNF-? and IL-1, may enhance osteoclast differentiation and activity in synergy with RANKL/RANK signaling. Therefore, the mechanisms and regulation of the effects of the inflammatory cytokines on osteoclastogenesis in OI will be the focus of this proposal. We hypothesize that increased TNF-? is a major molecular mechanism underlying enhanced osteoclastogenesis associated with OI. In the Aim 1 of the study we propose to assess frequency, phenotype, functional properties and NF-?B signaling pathway profile of OCPs in bone marrow and periphery of OIM mice. Based on our preliminary data we expect that TNF-? primes myeloid OCPs for increased and more rapid response to RANKL stimulation in OIM mice. In this aim we will assess contribution of TNF-? signaling to the increased osteoclastogenesis in OIM mice. In the aim 2 we plan to evaluate the effects of TNF-? antagonist (etanercept) treatment on the bone mass, bone structural parameters and fracture rate in growing OIM mice. This project will provide a pre-clinical evaluation of anti- TNF-? as a new therapeutic option for OI. The knowledge gained from this research will be invaluable for the development of future translational studies using human subjects and potential applications to treat human OI patients. TNF-? antagonist (etanercept) treatment has been FDA approved for other inflammatory conditions, meaning that if the results are positive, it could be rapidly translated into clinical practice.